Palonosetron is described as (3aS)-2-[(S)-1-azabicyclo [2.2.2] oct-3-yl]-2,3,3aS, 4,5,6-hexahydro-1H-benz [de] isoquinolin-1-one having the structural formula I and is administered as its hydrochloride salt (Aloxi).

Palonosetron hydrochloride is a white to off-white crystalline powder and is freely soluble in water. It contains two chiral centers and is synthesized as a single diastereomer wherein both have S, S absolute configurations. The first synthesis of Palonosetron hydrochloride is described in EP 0,430,190 A2 and its equivalent U.S. Pat. No. 5,202,333 by Berger et. al. The authors discuss a process wherein palonosetron hydrochloride (I) is prepared from immediate precursor intermediate (II) by way of its reduction at high pressure to diastereomeric palonosetron hydrochloride followed by crystallization of the resulting diastereomeric mixture two to three times from ethanol.

The problem features, albeit of essential significance of the disclosed process, are described below.
Firstly, the chemical purity of the diastereomeric palonosetrons obtained by the hydrogenation of intermediate II is not mentioned. Secondly the obtained diastereomeric mixture is purified to the desired (3aS, S) diastereomer by repeated crystallization from ethanol resulting in significant yield loss. Finally, the desired palonosetron hydrochloride (I) is contaminated with 1.0% or above of the undesired 3aR, S-diastereomer (Ia).
The authors also disclose a slightly revised process in Journal of Medicinal Chemistry, 1993, 36(18) wherein is described an additional example for the reduction of intermediate II with 10% Pd/C (62% wet w/w) in tetrahydrofuran under a hydrogen atmosphere for fifteen days. Here also there is no mention of the chemical purity of diastereomeric palonosetrons. Also the diastereomeric purity of the final product (I) is reported to be 99.00% only.
Another U.S. Pat. No. 5,510,486 by Robinson III et. al. provides a process for the preparation of palonosetron and its pharmaceutically acceptable salts, following the strategy in a general scheme 01.

This process providing palonosetron hydrochloride (I) by using different starting materials does not disclose the diastereomeric purity of the final product.
Another prior art U.S. Pat. No. 5,567,818 by Kowalczyk, also published in Heterocyles, 1996, 43(7) describes a process for the preparation of palonosetron hydrochloride (I) wherein intermediate (II) is converted to palonosetron hydrochloride (I) following a process essentially similar to those discussed in the earlier prior arts i.e EP 0,430,190 A2 etc. However the disclosed process affords palonosetron hydrochloride (I) showing only 99% diastereomeric purity.
Another publication Organic Process & Development 1997, 1, 117-180 by Bruce A. Kowalczyk & Norman H. Dyson, discusses hydrogenation of intermediate II to diastereomeric palonosetrons by various catalysts under different reaction conditions. Mentioned therein is the equilibration of undesired (3aR,S) diastereomer as its hydrochloride (Ia) to the desired palonosetron hydrochloride (I) via hydrogen activated palladium catalyst under a nitrogen atmosphere. The publication discloses the resulting product mixture of palonosetron hydrochloride (I) and the undesired (3aR,S) diastereomer (Ia) contaminated with ˜1.00% of intermediate II as its hydrochloride in one of the examples of equilibration. The amount of intermediate II or its hydrochloride present before equilibration or after reduction with various catalysts and under varying conditions can be envisaged by the conversion listed in the Tables 1 & 2 of this publication which indicate presence of a maximum of ˜82.0% and a minimum of 1.0% of the intermediate II or its hydrochloride although a sufficiently pure mixture of desired palonosetron hydrochloride (I) and its undesired 3aR,S diastereomer (Ia) has been employed for the equilibration reaction. However the publication does not mention anything on separation of the unwanted intermediate II from the diastereomeric palonosetrons. The palonosetron hydrochloride (I) produced in this publication has been reported to contain only 99.2% of the desired (S, S) isomer.
Another prior art US 2008/0058367 A1 describes a process for the purification of palonosetron or its salts. In this publication the crude reaction product after the reduction of intermediate II containing 52.61% palonosetron hydrochloride (I), 45.19% of its undesired 3aR,S-diastereomer (Ia) and 0.65% of intermediate II is purified by a cycle of operations described below which may appear remarkably cumbersome.
First step is slurry wash of the crude reaction product obtained after reduction with ethanol for 2.0 hours followed by filtration and suck drying for 3.0 hours to yield palonosetron hydrochloride (I) having 93.71% of the desired (3aS, S) isomer, 6.13% of the undesired (3aR, S) diastereomer (Ia) and 0.08% of the unreacted intermediate II.
Second step involves replacement of ethanol traces by suspending the above obtained palonosetron hydrochloride (I) in methanol and removing methanol completely by distillation at 55 to 60° C. Third step involves suspending again the so obtained palonosetron hydrochloride (I) in methanol, diluting it further with methanol, passing the obtained suspension through celite, concentrating the filtrate to a marked level, stirring the contents first between 25-35° C. then between 0-5° C. for 2.0 hours and then finally filtering the precipitated solid followed by vacuum drying. This leads to a palonosetron hydrochloride I having 99.72% of the desired (3aS,S) isomer, 0.18% of the undesired (3aR,S) diastereomer (Ia) and 0.04% of the intermediate II.
This publication also discloses a reprocessing method wherein the mixture of diastereomeric palonosetron contaminated with more than 1.0% of unconverted intermediate II obtained after reduction of intermediate II is resubjected to the hydrogenation reaction conditions and purified via the tedious purification process as discussed in the earlier texts to yield palonosetron hydrochloride (I) which is 99.75% pure by chiral HPLC.
Both the methods discussed in this publication have the following drawbacks. Firstly, the purification method used does not eliminate the unwanted intermediate II completely. The yield after performing the tedious purification process has not been disclosed. Nonetheless it may not be unreasonable to envisage a yield substantially below commercial acceptance.
The reprocessing method of resubjecting the crude mixture of palonosetron hydrochloride (I), its undesired (3aR, S) diastereomer (Ia) and intermediate of formula II wherein intermediate II as its hydrochloride is more than 1.00% to the hydrogenation conditions, as demonstrated by the authors, does not ensure lowering of the amount of intermediate II or its hydrochloride.
As seen in the discussed prior arts, various methods for the preparation of palonosetron and its pharmaceutically acceptable salts, and its purification from the undesired isomer and unreacted starting materials have been provided. However the issue of the complete removal of the unreacted intermediate II or its hydrochloride present in varying amounts in palonosetron or its hydrochloride (I) carried forward from the reduction step still remains in spite of efforts along this direction are reported in few prior arts, e.g., US 2008/0058367 A1 via tedious purification procedures without commensurate success.
Thus the need to develop an economically and operationally viable purification process to separate the unwanted intermediate II or its hydrochloride and the undesired 3aR, S diastereomer (Ia) efficiently from a crude mixture of palonosetron hydrochloride (I), undesired (3aR,S) diastereomer (Ia) and unreacted intermediate II to provide palonosetron hydrochloride (I) in substantially pure form is required.